Metabolic signature characterizes adherence to Mediterranean diet

The Mediterranean diet, plasma metabolome, and cardiovascular disease risk

Literature - Li J, Guasch-Ferré M, Chung W et al., - Eur Heart J. 2020 Jul 21;41(28):2645-2656. doi: 10.1093/eurheartj/ehaa209.

Introduction and methods

Intervention trials and prospective cohort studies have shown that adherence to the Mediterranean diet leads to health benefits [1-4]. However, metabolic responses to the same diet may vary between individuals. Metabolic profiles can be determined by measuring intermediate molecules and products of metabolism. This profile reflects the dietary intakes and other sources of variability in metabolism, such as genetic variations and diet-gut microbiome interplay in an individual [5,6]. Metabolic profiles may therefore be used to objectively assess adherence and metabolic responses to dietary patterns [7,8]. The present study identified and validated a metabolic signature reflecting adherence to a Mediterranean diet and examined whether this signature was associated with CVD risk.

The primary study cohort included 1859 participants from the Spanish PREDIMED trial, a study that examined the efficacy of two Mediterranean diet interventions over a control diet for primary prevention of CVD and T2DM [1,9]. The validation cohorts that were used in this study included 6868 participants from the US Nurses’ Health Studies (NHS) I and II, and Health Professionals Follow-up Study (HPFS) [10,11]. In PREDIMED, a validated 14-item Mediterranean Diet Adherence Screener (MEDAS) was used to assess adherence to the Mediterranean diet [12,13]. Data was available from 1859 participants at baseline and from 1556 participants at year 1 of intervention. Diet in NHS/HPFS was assessed using validated food frequency questionnaires (FFQs) [14]. The MEDAS score in NHS/HPFS was estimated using average dietary intakes from two FFQs. The plasma metabolomics profiling for PREDIMED and NHS/HPFS was performed using liquid chromatography-tandem mass spectrometry. Incident CVD was defined as the composite of non-fatal MI, non-fatal stroke and CV death from baseline through end of follow-up. Median follow-up was 4.8 years for PREDIMED, 22.3 years for NHS, 15.3 years for NHSII, and 17.6 years for HDFS.

Main results

  • A metabolic signature, comprising 67 metabolites, was identified and was significantly correlated with MEDAS in both PREDIMED and NHS/HPFS (PREDIMED year -1: r=31, P=3×10^-35; NHS/HPFS: r = 0.28, P=4×10^-118).
  • The metabolic signature included 45 lipid species and acylcarnitines, 19 amino acids, 2 vitamins and 1 xenobiotic.
  • A significant inverse association was observed between baseline MEDAS and incident CVD in multivariable analyses of the PREDIMED study (HR per SD increment in MEDAS=0.77, 95%CI 0.64-0.93, P=0.008). A statistically non-significant inverse association was observed between year-1 MEDAS and incident CVD (HR 0.87, 95%CI 0.71-1.05, P=0.15).
  • In multivariable analyses of the PREDIMED study, metabolic signatures at baseline and year 1 were both inversely associated with incident CVD (baseline signature: HR 0.71, 95%CI 0.58-0.87, P<0.001); year-1 signature: HR 0.72, 95%CI 0.57-0.92, P=0.008). Associations remained significant after adjustment for MEDAS or MEDAS components (baseline signature: HR 0.73, 95%CI 0.59-0.91, P=0.004); year-1 signature: HR 0.74, 95%CI 0.58-0.94, P=0.01).
  • In multivariable analyses of NHS/HPFS, baseline metabolic signature was significantly associated with CVD risk after adjusting for known risk factors and potential confounders (HR 0.85, 95%CI 0.76-0.94, P=0.001) and after further adjustment for MEDAS or MEDAS components (HR 0.85, 95%CI 0.77-0.95, P=0.004).
  • Metabolites associated with higher MEDAS, were more likely to be associated with a lower risk for CVD (especially higher intakes of olive oil, wine, and fish or seafood, and lower intakes of sweets and sugar sweetened beverages). On the other hand, metabolites associated with lower MEDAS were more likely to be associated with higher risk for CVD.
  • Mendelian randomization analyses showed that the genetically inferred metabolic signature was inversely associated with risk of CHD, total stroke and ischemic stroke (CHD: OR per SD increment in the genetically inferred metabolic signature = 0.92, 95%CI 0.91-0.94, P<0.001; total stroke: OR 0.91, 95%CI 0.88-0.94, P<0.001; ischemic stroke: OR 0.89, 95%CI 0.86-0.92, P<0.001).


This study identified a metabolic signature that reflects adherence to a Mediterranean diet and is associated with future CVD risk, independent of traditional risk factors. Metabolomics profiling could contribute to individualized approaches for dietary interventions.


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